This application entitled "Modulators of metabotropic glutamate receptor subtype 2 for cocaine dependence" is in response to RFA-DA-07-006. Cocaine addiction remains a major public health problem in the United States. To date, a safe and effective treatment for cocaine dependence has yet to be identified. Thus, there is great need to explore novel pharmacological treatments for cocaine dependence. We plan to use a multidisciplinary approach involving chemistry, in vitro pharmacology and behavioral assessment of novel compounds in rat models of cocaine dependence, withdrawal and reinstatement of cocaine-seeking behavior. Repeated cocaine exposure alters the function of Group II metabotropic glutamate receptors (mGluRs) that comprise mGluR2 and mGluR3. There have been relatively few selective compounds for mGluR2 and most of these compounds do not have good brain penetration. Here, we propose to design and synthesize new positive and negative allosteric modulators of mGluR2 that are systemically active in vivo and have good brain bioavailability (Specific Aim 1). Then, in Specific Aim 2, we will characterize these positive and negative mGluR2 allosteric modulators in in vitro assays of potency and selectivity. Further, we will assess potential off target effects of these compounds at other molecular targets in the brain. The pharmacokinetic profile and brain penetration of the most promising analogues will be evaluated in rats to facilitate selection of the best compounds for in vivo pharmacology studies. In Specific Aim 3, we will investigate the effects of mGluR2 positive and negative allosteric modulators in rat models of cocaine dependence (extended access to intravenous cocaine self-administration), reinstatement (discriminatory cue-induced reinstatement of cocaine-seeking behavior) and early withdrawal (elevations in intracranial self-stimulation thresholds during cocaine withdrawal) in rats. Additional experiments will compare the effects of the test compounds on behaviors motivated by a food reinforcer as an important aspect of drug screening for potential anti-addiction medications. It is predicted that mGluR2 positive modulators will decrease the reinforcing effects of self-administered cocaine in cocaine-"dependent" rats only, and attenuate cue-induced cocaine-seeking behavior. By contrast, administration of mGluR2 negative modulators would reverse affective signs associated with cocaine withdrawal. If mGluR2 positive or negative modulators are effective in one or several of these models, then we would achieve proof-of-concept for systemically active modulators of mGluR2 as potential novel pharmacotherapies to treat aspects of cocaine addiction in humans. Significance: The proposed studies will design and synthesize new chemical entities with high potency and selectivity for mGluR2 with good brain penetration, and potentially "therapeutic" effects in animal models of cocaine dependence. Thus, the proposed studies will provide new molecules to probe the function of mGluR2 in cocaine dependence and potentially novel therapeutic agents for the treatment of cocaine addiction in humans. The proposed research is a highly innovative, significant and timely multidisciplinary project that draws on the expertise of the research team and addresses the requirements of this RFA.